We hypothesized that diet-metformin (MET) promote successful live births in women with polycystic ovary syndrome (PCOS) by lowering hypofibrinolytic plasminogen activator inhibitor (PAI-Fx) during the 1st two trimesters of pregnancy. We studied 43 women with PCOS, 21 with live births, 22 with 1st trimester miscarriages. Women with BMI<25 or ≥ 25 kg/m2 were given a 2000 or 1500 calorie/day, high protein (26% of calories), low carbohydrate (44%) diet. Caloric restrictions were dropped after conception. The targeted MET dose was 2.55 g/day; 11 of 43 (26%) women tolerated only 1.5 g. Of the 21 live birth pregnancies, 19 (90%) took MET 2.55 g/day, 2 took 1.5 g. Of the 22 miscarriages, 13 (59%) took MET 2.55 g/day, 9 took 1.5 g, with fewer women in the miscarriage group taking 2.55 g/day, p = .034. Live birth and miscarriage groups did not differ (p>0.1) at pre-treatment (pre-Rx) study entry by median age (28 vs 30 years), BMI (33.6 vs 34.9), serum insulin (24 vs 20 μU/mL), HOMA insulin resistance (IR) (5.07 vs 4.42), HOMA insulin secretion (342 vs 240), PAI-Fx (18.8 vs 11.7 u/mL), or race (95% vs 100% white). At pre-Rx baseline, in the 21 live birth pregnancies, median PAI-Fx was 18.8 u/mL, fell on MET-diet to 11.4 at the last pre-conception visit, fell to 8.6 at the end of the 1st trimester, and was 11.7 at the end of the 2nd trimester (p<.05 for all). At pre-Rx baseline, in the 22 miscarriages, median PAI-Fx was 11.7 u/mL, rose on MET-diet to 13.9 at the last pre-conception visit, and then fell to 8.3 at the end of the 1st trimester (all p>.05). In the live birth group, on diet-MET for 12 months pre-conception, PAI-Fx fell 54% (p =.051) from pre-Rx baseline to the last pre-conception visit. In the miscarriage group, on diet-MET for 9 months pre-conception, PAI-Fx rose 19% from pre-Rx baseline to the last pre-conception visit, differing from the live birth group (p = .01). From pre-Rx baseline to the 1st trimester, live birth and miscarriage groups both lost weight (9.7% [p<.0001], 4.7% [p = .0006]), without group differences in weight loss (p = 0.1). From pre-Rx baseline to the 1st trimester, serum insulin fell 61% (p = .009) and HOMA IR fell 60% in the live birth group (p = .036), but fell less (28%, p = .3; 31%, p = .3) in the miscarriage group, with reductions greater in the live birth group (p = .012, p = .031). In PCOS, major reductions in PAI-Fx (54%) on diet-MET from pre-Rx baseline to the last pre-conception visit are associated with favorable pregnancy outcomes, whereas increments of PAI-Fx on diet-MET (19%) are associated with miscarriage, with high PAI-Fx contributing to placental insufficiency.
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